This study was intended to identify changes caused by short-term reduced feed intake in rats such as may occur with unpalatable feed or other forms of anorexia. For 2 wk, groups of rats (10/sex/group) were fed ad libitum (control group) or given 75% (mildly restricted group), 50% (moderately restricted group), or 25% (severely restricted group) of the amount of feed eaten the day before by controls. The control group and mildly restricted group grew steadily, but the terminal body weights of the mildly restricted group (both males and females) were only about 80% of controls. The moderately restricted group did not grow during the first week but grew slightly during the second week (terminal body weights about 65% of control). The severely restricted group lost weight throughout the study (terminal weight about 40% of control). Restricted groups exhibited hemoconcentration directly related to the degree of feed restriction. White blood cell counts were reduced (principally due to lymphopenia) in severely restricted rats. Platelet counts were decreased in all restricted groups. Total serum protein concentration was reduced (decreased globulins) in all female restricted groups and in the severely restricted males. The severely restricted rats had increased serum bilirubin, electrolyte derangements, and (in females only) decreased cholesterol. Thymus and liver weights (absolute and relative) were decreased in the moderately and severely restricted groups. All the feed-restricted groups had an increased incidence of superficial gastric erosions. The mildly and moderately restricted groups had slightly decreased hematopoietic tissue in sternal bone marrow, while the severely restricted group had bone marrow necrosis, thymic atrophy, and mild testicular degeneration. Findings in the severely restricted group were distinct from those in the other groups on the basis of their severity and were considered adverse. Changes in the mildly and moderately restricted groups were considered adaptive and innocuous since feed restriction of this degree has historically been associated with increased longevity and decreased disease incidence in chronic studies.

Endothelins are a class of peptides that are produced by and elicit responses in many tissues. A growing literature documents the presence and effects of endothelins in bone. Both endothelinA and endothelinB receptors have been demonstrated in osteoblastic cells by ligand binding. Major signal transduction pathways for endothelin in bone cells appear to be stimulation of phospholipid turnover, by activation of A, C and D phospholipases, stimulation of calcium flux from intracellular and extracellular stores and activation of tyrosine kinases. Endothelins also modulate calcium signaling elicited by other agents in osteoblastic cells. The parathyroid hormone-stimulated calcium transient in UMR-106 cells is enhanced by endothelins, acting through an endothelinB receptor, whereas the parathyroid hormone-stimulated increase in cyclic AMP is inhibited by endothelins. Phenotypic responses to endothelin-1 include changes in alkaline phosphatase activity, stimulation of osteocalcin and osteopontin message, stimulation of collagen and noncollagenous protein synthesis, inhibition of osteoclast motility and stimulation of prostaglandin-dependent resorption. Endothelin-1 also enhances the interleukin-1-induced increase in interleukin-6. Endothelins can also potentially affect calcium metabolism through their actions to inhibit the secretion of parathyroid hormone.

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Bemitradine (SC-33643), a diuretic antihypertensive agent, was studied for its carcinogenicity in a 2-year bioassay in Charles River CD rats via dietary admix at dosages of 50, 150 and 450 mg kg-1 for up to 97 weeks (after which they were followed for eight additional weeks without treatment). Body weights were decreased compared to controls: 5-15% in the female and 10-12% in the male dosage groups by week 105 of the study. Prolactin values were significantly increased in 150 and 450 mg kg-1 females. The compound caused significant increased incidences of liver, thyroid (both sexes) and mammary (females only) neoplasms. The metabolism of bemitradine was studied in both rats and man. Bemitradine and its primary metabolite (SC-36741; desethylbemitradine) were tested and found to be non-genotoxic in Ames, rat primary hepatocyte UDS, CHO/HGPRT, CHO cytogenetics, in vivo mouse micronucleus and mouse lymphoma TK+/- (bemitradine only) assays. Finally, in an altered hepatic foci (Y-glutamyl transpeptidase positive) promotion assay in female Charles River CD rats, bemitradine was found to be a promotor, though not as potent as phenobarbital. We concluded that bemitradine (which has been dropped from development) is a non-genotoxic carcinogen which appears to act by a hormonally modulated promotional activity in inducing tumors in the liver and mammary glands. Tumors seen in the thyroid were probably secondary to the effects of bemitradine on metabolism.

Research and Development, Skokie, Illinois, U.S.AActisomide (SC-36602) is a chemically novel antiarrhythmic drug that blocks sodium channels in a manner similar to lidocaine and mexiletine. In preclinical studies, actisomide was unusually well tolerated and had very little negative inotropic activity in comparison to other class I antiarrhythmic agents. The potential for a broad spectrum of antiarrhythmic activity for this new drug is supported by the demonstration of effectiveness against both atrial and ventricular arrhythmias in experimental models.This review provides a summary of the chemical features, preclinical pharmacology, pharmacokinetics and metabolism, toxicology, and early clinical data for actisomide. Actisomide is the U.S. adopted name (USAN) for the compound numbered SC-36602 by G. D. Searle. Both designations are used in this review.CHEMISTRY Actisomide (Fig. 1) was selected for development from a series of chemically related structures (3) on the basis of its antiarrhythmic activity in experimental models, its favorable side effect profile (especially the relative absence of negative inotropism and anticholinergic activity), and its wide safety margin. The chemical name of actisomide is (k)-truns-4-{ 2-[bis-( 1 -methylethyl)-amino]-ethyl}-4,4a,5,6,7,8-hexahydro-l-methyl-4-phenyl-[ 3H]-pyrido[ 1,2-c]-pyrimidin-3-one. The molecular weight of actisomide is 369.55, the empiric formula is C23H35N30, and the melting point is 20 1-202°C. For pharmacologic solutions, the free base of actisomide was readily dissolved in distilled water with dropwise addition of HCl followed by neutralization with NaOH. The distribution coefficient for actisomide in octanol/buffer is 0.092. PRECLINICAL PHARMACOLOGY Antiarrhythmic ActivityThe antiarrhythmic effects of actisomide have been studied in canine models of coronary ligation-induced arrhythmias (9, ouabain-induced arrhythmias (5), and